Normal skin's curiously abnormal genome: Within every tumor, a battle is being waged. As individual tumor cells acquire new mutations that promote their survival and growth, they clonally expand at the expense of tumor cells that are “less fit.” Martincorenaet al.sequenced 234 biopsies of sun-exposed but physiologically normal skin from four individuals (see the Perspective by Brash). They found a surprisingly high burden of mutations, higher than that of many tumors. Many of the mutations known to drive the growth of cutaneous squamous cell carcinomas were already under strong positive selection. More than a quarter of normal skin cells carried a driver mutation, and every square centimeter of skin contained hundreds of competing mutant clones.Science, this issue p.880; see also p.867

Epithelial Defense Force: The nature of the cells that maintain and heal the epithelium lining the esophagus has been controversial. Doupé et al. (p. 1091 , published online 19 July; see the Perspective by Kushner ) show that, unlike many other tissues, mouse esophagus is devoid of slow cycling stem cells. Instead, the epithelium is maintained and repaired by a single population of proliferating cells that can switch rapidly from homeostatic behavior into “repair mode” in the vicinity of a wound.

Skin cancer risk varies substantially across the body, yet how this relates to the mutations found in normal skin is unknown. Here we mapped mutant clones in skin from high- and low-risk sites. The density of mutations varied by location. The prevalence of NOTCH1 and FAT1 mutations in forearm, trunk, and leg skin was similar to that in keratinocyte cancers. Most mutations were caused by ultraviolet light, but mutational signature analysis suggested differences in DNA-repair processes between sites. Eleven mutant genes were under positive selection, with TP53 preferentially selected in the head and FAT1 in the leg. Fine-scale mapping revealed 10% of clones had copy-number alterations. Analysis of hair follicles showed mutations in the upper follicle resembled adjacent skin, but the lower follicle was sparsely mutated. Normal skin is a dense patchwork of mutant clones arising from competitive selection that varies by location. Significance: Mapping mutant clones across the body reveals normal skin is a dense patchwork of mutant cells. The variation in cancer risk between sites substantially exceeds that in mutant clone density. More generally, mutant genes cannot be assigned as cancer drivers until their prevalence in normal tissue is known. See related commentary by De Dominici and DeGregori, p. 227. This article is highlighted in the In This Issue feature, p. 211

Single stem cells, including those in human epidermis, have a remarkable ability to reconstitute tissues in vitro, but the cellular mechanisms that enable this are ill-defined. Here we used live imaging to track the outcome of thousands of divisions in clonal cultures of primary human epidermal keratinocytes. Two modes of proliferation were seen. In ‘balanced’ mode, similar proportions of proliferating and differentiating cells were generated, achieving the ‘population asymmetry’ that sustains epidermal homeostasis in vivo. In ‘expanding’ mode, an excess of cycling cells was produced, generating large expanding colonies. Cells in expanding mode switched their behaviour to balanced mode once local confluence was attained. However, when a confluent area was wounded in a scratch assay, cells near the scratch switched back to expanding mode until the defect was closed. We conclude that the ability of a single epidermal stem cell to reconstitute an epithelium is explained by two interconvertible modes of proliferation regulated by confluence.

A neglected femoral neck fracture is one where there has been a delay of more than 30 days to seek medical help from the time of the original injury. Among the spectrum of femoral neck fractures, the neglected fracture in a young adult (age <60 years) is one of the most challenging to treat if femoral head salvage is attempted. The main complication is avascular necrosis (AVN) of the femoral head with most reported incidences being <15% (range 0% to 67%), which is similar to the complication rate with non-neglected femoral neck fractures. This review consolidates our current knowledge about the problem, discusses the various treatment options and compares the published long-term results. There are no clear guidelines for management of neglected femoral neck fractures, although multiple methods have been used with varying success. Bone grafting or internal fixation in isolation does not provide a satisfactory outcome. Osteotomy has given better outcomes (AVN 6% to 17%, non-union 0% to 15%), but mechanical changes at the femoral neck may lead to a persistent painful hip. Bone grafting with internal fixation has emerged as a reliable method with good long-term functional outcomes.

#### Summary points Burn injuries are an important global health problem. Most simple burns can be managed by general practitioners in primary care, but complex burns and all major burns warrant a specialist and skilled multidisciplinary approach for a successful clinical outcome. This article discusses the principles behind managing major burns and scalds using an evidence based approach and provides a framework for managing simple burns in the community. #### Sources and selection criteria We searched Medline, Ovid, Burns, and the Cochrane Library until June 2008 for randomised controlled trials, systematic reviews, evidence reports, and recent evidence based guidelines from international burn associations. Annually in the United Kingdom, around 175 000 people attend accident and emergency departments with burns from various causes (box 1).1 This represents 1% of all emergency department attendances, and about 10% of these patients need inpatient management in a specialist unit.2 A further 250 000 patients are managed in the community by general practitioners and allied professionals. Of patients referred to hospital, some 16 000 are admitted, and about 1000 patients need active fluid resuscitation. The number of burns related deaths average 300 a year.1 #### Box 1 Some important causes of burns and scalds Globally, the World Health Organization estimates that 322 000 people die each year from …